This application is a request for a NIMH Physician Scientist Award. Having just completed his psychiatric residency at the University of Chicago, Dr. Alan Louie is seeking to continue his laboratory research training in neuropsychopharmacology so that he will be able to utilize his clinical expertise to investigate molecular mechanisms of psychoactive drugs and of mental illnesses. A five year program is proposed at the Langley Porter Psychiatric Institute in the UCSF Department of Psychiatry. The program includes course work, training in laboratory research and a specific research project. Course work during the first year and a half will be taken in the UCSF graduate division and will cover topics in the neurosciences and molecular pharmacology. Concurrent with this course work, research training in the laboratory of Dr. Horace Loh, Professor of Psychiatry and Pharmacology, will begin on a part-time basis and will shift to full-time after the courses are completed. Initially, laboratory techniques relevant to biological psychiatry research will be mastered such as receptor binding assays, radioimmunoassays, high pressure liquid chromatography, etc. Later, Dr. Louie will engage in a research project to study the molecular mechanisms of narcotic and endorphin tolerance. His project will address the hypothesis that one mechanism of opioid tolerance involves an alteration of the receptor. In order to demonstrate that the receptor is altered, as opposed to some other cellular component beyond the receptor, a reconstitution methodology will be developed to test the functioning of the receptor. This methodology will allow solubilization and isolation of the opioid receptor followed by its reconstitution into the membrane of a cultured cell, a neuroblastoma x glioma hybrid cell. Since opioid receptors have been shown to couple to the adenylate-cyclase-second-messenger system in these cells, the ability of the reconstituted receptor to couple with the cell's adenylate cyclase will serve as a measure of the receptor's functioning. Thus, the cultured cell will provide an assay of opioid receptor function. Such an assay will be of value not only in investigating opioid receptor function in a tolerant state but also has implications for studying the functioning of opioid receptors in various psychiatric disease states. The proposed five year training program should provide Dr. Louie, a psychiatrist, with excellent scientific training in neuropsychopharmacology and preparation for independent investigation at the interface of basic and clinical sciences.